PURPOSE: To describe the concerns raised by health plan members, providers and purchasers related to studying the comparative effectiveness of therapeutics using cluster randomized trials (CRTs) within health plans. An additional goal was to develop recommendations for increasing acceptability. METHODS: Eighty-four qualitative in-depth telephone interviews were conducted; 50 with health plan members, 21 with providers, and 13 with purchasers. Interviews focused on stakeholders' concerns about and recommendations for conducting CRTs in health plans. RESULTS: Members expressed concerns that CRTs might compromise their healthcare. Providers and purchasers recognized the value of and the need for comparative effectiveness research. Providers expressed concerns that they would not have sufficient time to discuss a CRT with patients, and that participation in such a study could negatively impact their relationships with patients. Purchasers would want assurances that study participation would not result in members receiving lesser care, and that benefits would remain equitable for all members. CONCLUSIONS: This study provides insight into how health plan members, providers and purchasers might react to a CRT being conducted in their health plan. The recommendations reported here provide guidance for researchers and policy makers considering this methodological approach and suggest that with sufficient preparation and planning CRTs can be an acceptable and efficient methodology for studying the comparative effectiveness of therapeutics in real world settings.